Malaria parasites cause ~1.2 million deaths annually. Cerebral malaria (CM) is the most severe manifestation of malaria and results in decreased sensorium, coma, death, and in survivors lasting neurological complications. Cerebral malaria pathophysiology is thought to center along the vascular endothelium and is characterized by increased inflammatory cytokines, vascular leakage and a high parasite burden both in the blood stream and sequestered along microvascular walls. Human malaria is caused by five species of the Plasmodium parasite; of these P. falciparum is the deadliest and the only species which causes cerebral malaria. The specific features of P. falciparum infection that lead to cerebral malaria are unclear. One distinguishing feature of P. falciparum infection is the parasite's extracellular secretion of histidine rich protein II (HRPII). HRPII is produced by all natural isolates of P. falciparum and can be detected at high concentrations (> 1 ug/mL) in the bloodstream of patients. It has also been seen lining microvascular endothelial walls in post mortem analyses. Previous studies from our laboratory show that HRPII binds to soluble glycosaminoglycans (GAGs) such as heparin, heparan sulfate, and dermatan sulfate with high affinity. Cerebral malaria is marked by a pro-inflammatory environment, including an increase in chemokines CXCL9,10,11 and CCL3,4,5. Chemokines are small, positively charged proteins that interact with negatively charged cell surface GAGs to generate local gradients that guide leukocyte migration. Our preliminary data further highlight that HRPII can also specifically interact with cell surface GAGs. Mice deficient in receptors for these chemokines do not develop cerebral malaria. We hypothesize that by binding GAGs, HRPII perturbs chemokine accumulation along endothelial cells and thereby prevents effective, timely migration and activation of innate and adaptive immune cells. We will assess the impact of HRPII on both brain endothelial cell surface chemokine display and resulting effector cell migration. Our experiments also revealed that HRPII has a cytotoxic effect on a brain microvascular endothelial cell line, characterized by cell surface blebbing. Upon further exploration, we observed an increase in permeability of brain microvascular endothelial cell monolayers and a decrease in their trans-endothelial cell resistance in the presence of HRPII. We hypothesize that HRPII may further contribute to cerebral malaria by compromising the integrity of the blood brain barrier. Are these modifications mediated by cellular death, altered polarity, loss of tight junctions or another mechanism; and is this phenomenon contributing to the development of cerebral malaria in vivo? We propose that HRPII plays a central role in the progression to cerebral malaria. Based on its high affinity for cell surface GAGs and associated cytotoxicity, we hypothesize that HRPII contributes to the pathophysiology seen in patients with cerebral malaria as a consequence of its interactions with endothelial cell surfaces.